Salivary gland hypofunction is a major oral health problem that affects the quality of life for several million people in the USA. A variety of conditions can resulting in the loss of salivary acinar cell secretory function including systemic diseases such as Sjogren's Syndrome (an autoimmune disease), X-ray irradiation, cancer chemotherapy, psychological factors, malnutrition, pharmacological induced xerostomia and oral cancer. All of these disease conditions or treatments have the potential to alter normal salivary acinar cell homeostasis and to accelerate the entry of the salivary gland acinar cells into apoptosis. A fundamental understanding of the molecular events involved in salivary gland acinar apoptosis is required if we are to fully comprehend the specific mechanisms involved in salivary gland hypofunction. This information is also essential for the development of new treatment modalities that have the potential to block or delay the toxic effects of these various disease conditions and treatments on normal acinar cell function. The principle objective of this project is to investigate and determine at the molecular level the precise function of the two major cellular protein families that play a central role in the initiation signaling and execution of acinar cell apoptosis. The two critical regulatory protein families are the caspase and the Bcl-2 family of proteins. We will determine their level of expression, subcellular distribution, level of phosphorylation and their functional activity during t he onset and duration of acinar cell apoptosis elicited by specific apoptotic stimuli. These studies will be performed using primary cultures of rat parotid and sub-mandibular acinar cells and immortalized rat parotid and sub-mandibular acinar cell lines. The identification and characterization of these two critically important protein families will provide new basic scientific information and insights for the development of new therapeutic approaches to suppress aberrant acinar cell apoptosis, with the long term objective to improve the quality of life for millions of affected individuals.